HMGB2 Deficiency in Bone Marrow Mesenchymal Stem Cells Promotes Age‐Related Osteoporosis by Inhibiting Osteoblast Differentiation via Inflammatory Factors

Nov 13, 2025FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Lack of HMGB2 in Bone Marrow Stem Cells May Promote Age-Related Bone Loss by Blocking Bone-Building Cell Development Through Inflammation

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Abstract

HMGB2 overexpression reverses senescence-mediated osteogenic impairment in bone marrow mesenchymal stem cells.

Cellular senescence is associated with reduced osteogenic differentiation and proliferation of bone marrow mesenchymal stem cells.
In vivo studies show a strong correlation between decreased HMGB2 levels and the progression of osteoporosis in aging mice.
HMGB2 promotes bone formation by inhibiting the inflammatory cytokine TNF-α and stabilizing the long non-coding RNA TUG1.
The stabilization of TUG1 by HMGB2 leads to the suppression of pro-inflammatory cytokines IL-1β and IL-6.
This study identifies a novel regulatory axis involving HMGB2 and TUG1 that may influence stem cell differentiation.

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With the global rise in osteoporosis due to aging, impaired osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) has emerged as a critical pathogenic factor. Although high mobility group box 2 (HMGB2) is implicated in BMSC aging and organismal senescence, its mechanistic role in osteoporosis remains unclear. Here, we investigate HMGB2's regulatory effects on BMSC osteogenic differentiation under aging conditions. Using an HO-induced BMSC senescence model, we demonstrate that cellular senescence suppresses osteogenic differentiation, evidenced by reduced expression of osteogenic markers and diminished proliferation. Notably, HMGB2 overexpression reversed senescence-mediated osteogenic impairment. In vivo studies of ovariectomy-induced aging mice revealed a strong correlation between HMGB2 downregulation and osteoporosis progression, confirmed via immunohistochemistry. Mechanistically, HMGB2 promotes osteogenesis by directly suppressing TNF-α and stabilizing the long non-coding RNA TUG1, which subsequently inhibits pro-inflammatory cytokines IL-1β and IL-6. This dual regulatory pathway highlights HMGB2's role in counteracting senescence-driven osteogenic decline. Our study not only elucidates a novel HMGB2/TUG1 axis governing stem cell differentiation but also identifies HMGB2 as a promising therapeutic target for combating osteoporosis. 2 2

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HMGB2 Deficiency in Bone Marrow Mesenchymal Stem Cells Promotes Age‐Related Osteoporosis by Inhibiting Osteoblast Differentiation via Inflammatory Factors

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